Epimerization of halogenated compounds containing cyclopentanopolyhydrophenanthrene nucleus



2352.539 MERIZAHQN ERHA O ENA ED Q TA N1NG .CYCLQPENTANPOLYHYDROPHENANTIRENE NUCLEUS- John T. Bay, North Plainfield, andCharles M. Smith,

This invention relates to halogenated steroids and part cularly to theconversion of steroids having halo groups attached to positions of thecyclopentanopolyhydrophenanthrene nucleus in one configuration to thecorresponding steroid having groups at such positions in the oppositeconfiguration. s i a This application is a continuationin-part oi ourcopendin'g application Serial No. 393,002, filed November 18, 1953, nowabandoned; I a

There are two types of geometrically distinct carbonhydrogen bonds whichcan be distinguished in cyclohexane. Six of the bonds lie parallel tothe threefold symmetry ofthe ring (Iland have been designated polar. Theother six carbon-hydrogen bonds (H) which are not so oriented, have beencal-ledfequatorial.

This distinction can be represented structurally asfollows:

In the cyclopentanopolyhydroplrenanthrene nucleus there are twoconformations HI and-IV of trans- '-A/;B and cis =A/B. These can berepresentedstructuraily as follows:

a and B configurational nomenclature can be summarized as shown in TableA.

United States Patent 2,852,539 Fatented Sept- 1958 TABLE A Tra'ns A/BCis=nlB Position d B a I g p e e 1 P P :e .e e P P P a at--.P(A);,-e"(B') P e P e P e P I P P p P 2(A): P(B)' 11 g P v e P P 3+ eun- This term has significance relative to the C ring'only.

The halogenation of steroids results. in the formation of a mixture ofepimers of the product. These epimei's are characterized as being in thea or the [3 configuration. The desired halogenated .product is usuallyonly one of the epimers. The epirner formed in the largest quantityvaries since in equilibrium controlled. reactions the stable epimerpredominates while in rate controlled reactions the polar is formedfaster, Thesprac'ti'cal resultsof the formation of the epimer'i'cduction in yield of the idesired product,

. It has been suggested to treat steroids groups attached to the carbonatom whichis alpha to a keto group in thecyclopentanopolyhydrophenanthrene nucleus with hydrobromic acid toconvert the steroid to an equilibrium mixture of epimers. The treatmentto cause enolization will be effective only if the product treatedresulted from a rate controlled reaction and not equilibrium controlled.

An. illustration of the formation of epirn'ers is the bromihati'on orchiorinatiorl of a 3-ketopregi1ane at the fourth carbon atom. Thisreaction is an important step in the preparation of cortisone,hydrocortisone and similar related compounds which is usually carriedout near the end of the long and involved synthesis. The 4-halo-3-ketopregnane is then dehydrohalogenated to form the corresponding4-pi'egnene-3 ol. The formation of the 4,5-double bond by theelimination of hydrogen halides is limited to 4;;i-halo groups whenusing semi-carbazide to protect the hem group since the 4a-halo group isreduced. The formation, therefore, in the halogenation process of theepi-meric 4cc-h310 pregnant: results in a lower yield of the desiredproduct. This reduction in yield due to the formation of the 4a-halopregnane is particularly disadvantageous considering that this stepoccurs nearly at the end of a long and involved synthesis which requiresthe employmentof expensive starting ma- 'teri'als and a multiplicity ofchemical equipment, reag nts and solvents.

An object of the invention is to provide a process for converting'ste'riods' c ntaining halo groups in the polar configura ion tosteroids containing halo, groups in the equatorial configuration.Another object is to provide such a process wherein the conversion takeslace in approximately quantitative yield. Other objects andthe-advantages of the invention will appear hereinafter. H

According to the present inventionit has been discovered thatsteroidshaviri halo groups attach-ed to the eyclopeiitahopolyhydrophenahthrene nucleus at aos'itio'n of the ring in the polarconfig ration 'ca'n be converted [to the corresponding steroids having ahalo roup at sucha "such a position in the equatorial eehfi uratie'n by'reaet- 'miXture is the reing with a salt which is capable of furnishingchloride, bromide or iodide ions in solution, under substantiallyneutral conditions and specifically non-acid conditions. This conversiontakes place in substantially quantitative yield.

The process of this invention is particularly suited to the treatment ofmixtures of epimeric halogenated steroids to convert the halo groups inthe polar configuration to halo groups in the equatorial configuration.Such epimeric mixtures are usually formed as a result of anyhalogenation process. The mixture of epimers can be reacted directlywith a halide salt to carry out the conversion without separating theepimers. In this manner almost quantitative yields of the halo-steroidshaving the halo groups in the equatorial configuration are obtained.When an iodide salt is reacted with a steroid having a bromo or chlorogroup in the polar configuration, the bromo or chloro groups arereplaced by an iodo group in the equatorial configuration; l'l'hesteroid having the iodo group can be readily recovered and convenientlyreduced to remove the iodo group thereby forming the starting materialfor the halogenation process and substantially increasing the yield ofthe desired steroid.

In a preferred embodiment of the invention an epimeric mixture of a4-bromo-3-keto or a 2,4-dibromo-3-ketopregnane, both of the normalseries, is reacted in a sub stantially neutral solution with a saltyielding bromide ions in the solution. It is believed that the bromideions cause the conversion of pregnanes having the a-bromo groups (polar)to pregnanes having ,B-bromo groups (equatorial). In this manner,substantially quantitative yields of the desired4;3-bromo-3-ketopregnane or 25,413-

dibromo-3-ketopregnanes are obtained. These reactions In a similarmanner using a chloride salt, the products produced also have the halogroup in the p-configuration. When an iodide salt is used the reactionwith the epimeric mixture results in the replacement of the bromo groupsin the a-configuration with iodo groups in the fi-configurzition. Theiodo substituted steroids can be conveniently separated and then reducedto remove the iodo group. This process, therefore, provides a simple andeconomical method of increasing the yield of the desired brominatedsteroid.

The reaction is preferably carried out by the addition of the steroidhaving halo groups in the polar configuration to a polar solventcontaining the halide salt. Suitable solvents are lower aliphaticketones, alcohols, esters, amides, nitriles, halogenated hydrocarbons ormixtures of such solvents with water. Typical examples of these solventsare acetone, butanol, methylacetate, dimethylformamide,dimethylacetamide, formamide, acetonitrile and mixtures of acetonitrileand chloroform. The process of this invention is not limited to thetreatment of the halogenated products from any particular process forthe halogenation of steroids, but can be applied to any such brominationprocess to increase the yield of the steroids having halo groups in theequatorial configuration.

Any halide salt can be used which is capable of furnishing chloride,bromide or iodide ions (halogens having atomic weight of from 35 to 127)in neutral solutions. The salts are preferably those in which the cationportion can be an alkali or alkaline earth metal ion, an ammonium orsubstituted ammonium ion or an amine salt. Typical examples of suchsalts are calcium chloride, sodium bromide, sodium chloride, potassiumbromide, potassium chloride, calcium bromide, magnesium bromide,magnesium chloride, sodium iodide, calcium iodide, ammonium bromide,ammonium chloride, magnesium iodide, tetramethyl ammonium bromide,tetramethyl ammonium chloride, pyridine hydrobromide, pyridinehydrochloride and pyridine hydroiodide. The salt is preferably used inthe range of approximately 10 to 40% based on the weight of the steroid.The salt is preferably soluble in the reaction media.

The treatment with the salt proceeds quite slowly at room temperatureand to achieve the best results it is preferred to carry out thetreatment at approximately 50 to 60 C. In a preferred procedure anaqueous acetone solution of a 3-keto-4a-bromo-steroid and sodium bromideis heated under reflux for approximately five hours.

The process of this invention as previously indicated can be applied toan epimeric mixture formed by any bromination process. Although theprocess is particularly applicable to the bromination products of3-ketosteroids it can be applied to steroids containing other functionalsubstituents attached to the steroid nucleus as well as steroidscontaining more than one halo group. Thus, keto groups may be presentsuch as at the 3,11 and ZO-positions, hydroxy groups at the 11, 17 and2l-positions, acyloxy groups of the formula where R is a hydrocarbongroup containing from one to eight carbon atoms such as alkyl groups, asfor example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl andoctyl; alicyclic groups, :as for example cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; aryl groups, as for example phenyl, benzyl,toluyl, phenyl ethyl and phenyl propyl, such as at the 2l-position andhalo groups such as at the 2, 4, 5, 6, 7 and 9-positions. Representativeof such steroids are 4-bromo-pregnane-l7a,21-diol- 3,11,20 trione 21acetate; 4-bromo-pregnane-l7a,2ldiol-3,20-dione-2l-acetate;4-bromo-pregnane-2Lot-3,20- dione-Zl-acetate; 4-bromo-pregnane-2 l-ol-3l 1,20-trione- 2l-acetate; 4-bromo-pregnane 3,11,20 trione; 3-keto-4-bromo-cholanic acid; 4 bromo pregnane-l7m-ol-3-one;3-keto-4-bromo-etiocholanic acid; 2,4-dibromo-pregnane- 17:1,21 diol3,11,20 trione-Zl-acetate;2,4-dibromopregnane-l7a,21-diol-3,20-dione-2l-acetate;2,4-dibromopregnane-21-ol-3,20-dione-2l-acetate;l-chloro-pregnanel7a,21-diol-3,11,20-trione-2l-acetate; 4-chloropregnanc- 17a,2l-diol-3,20-dione-2l-acetate; 4-chloro pregnane-Zl01-3,ZO-dione-Zl-acetate; 4-chloro-pregnane-2l-ol-3,l l ,20-trione-Zl-acetate; 4-chloro-pregnane ll .l7a,2l trione- 3,20dione-2l-acetate; 4-chloro-pregnane-3,l1,20-trione;3-keto-4-chloro-cholanic acid; 4-chloro-preguane-l'7a-ol- 3-one; 3-keto4 chloro-etiocholanic acid; 2,4-dichloropregnane l7rx,21 diol 3,11,20trione-Zl-acetate; 2,4-

dichloro pregnane-l7e,21-diol-3,20-dione-2lacetate and,

2,4-dichloro-pregnane-21-ol-3,20-dione 21 acetate, and4-bromo-1-pregnene-l7a,2 l-diol-3,20-dione-2 l-acetate.

illustration:

assesses s The following examples are iven .ror pur oses of Exam le] Asolution of 210 ml. of 1.00 N-bromine percent excess) in glacial aceticacid,' which contained 8.2 grams of anhydrous sodium acetate, was addeddropwise at room temperature with vigorous stirring to 0.100 mole ofpregnane-17a-ol-3,11,20-trione-21-acetate in 2000 ml. of acetic acidwhich contained ml. of 0.70 N hydrogen bromide in acetic acid. Thebromine solution was added during an interval of 30 minutes. Water wasadded until crystallization started and the solution was diluted to 7.3liters. The product, 4-bromo-pregnane-17a ol=3,11,20- trione-ZI-a'cetatewas filtered from the solution M 96.5 (acetone).

Example 2 dried product had a rotation of 110 (1% acetone) This productwas converted to cortisone in 13" to or greater yields than could beobtained usin the stare ing material of 965 rotation.

Example 3 p The conversion of the 4-bromo-pregnane-1 7a,21-diol-3,11,20-trione-2l-acetate formed accordingto Example 2 to cortisoneacetate is efiectedas follows: a mixture of 25 grams of the bromocompound, 775 cc. ofichlorofdrrn and 1294 cc. of butanol is prepared. Tothis mixture is added 7.75 grams of semicarba'zide as the free base andthe resulting mixture stirred for two hours at room temperature. Thereaction inixtnre is then concentrated in vacuo to a volume ofapproximately 250 ml. and subse- 'quently diluted with a solution of 200cc; of eth'anol and 250 cc. of water and allowed to' stand for thirtyminutes. The 3-s'ernicarbazone of cortisone acetate which is obtained asa solid product is filtered and washed free of halide ion. The productthus obtained is dissolved in a mixture 'of 475 cc. of acetic acid, 225cc; of water; and 10 cc. of pyruvic acid and stirred for 24 hours atroom temperature. The product, cortisone acetate, isconveniently'recovered by extraction with chloroform followed bycrystallization from acetone. The yield of cortisone acetate was 89%Using this same procedure the 4-bromo-p'reg'nane-17a,21-diol-3,11,20-trione 21 acetate 7 ([ct] =96.5 1% acetone) obtainedaccording to Example 1 was converted to cortisone acetate and the yieldwas 75%.

Example '4 The following table shows the results of tests made todetermine the applicability of a variety of solvents to the treatment of10.0 grams of crude 4-br0mo-pregnane-17a,21-diol-3,11,20-trione-2l-acetate obtained according to Example 1with 2.14 grams of sod um bromide. A

reaction time of only one hour for each test solvent was TABLE B' a v mp[as Solvent Amount,- Starting, (Afterl cc. degrees Hour),

degrees .Acetona V 250 9'6. 6 100. 0 hcetonewaternntn 300130 96. 6 103.0 t-Butanol-chloroform 250/ 96, 6 99. 2 Diniethylformainide 2 96.6 10820Atzefdnit'rile-chloroform. 150/100 96; 8 101 0 Exd'ntple' 5 A solutionof 24.2 grams of crude -4=bromo=lpregnane-. 3,11,20-trione-17,21diol-21-acetate (obtained by reacting the pregnane with broinineinaceticacid 'andin the presence of a small quantity of hydrogen bromide.) and3.7

grams of sodium iodide in 500 cc. of acetone was stirred for four andone-half hours at room temperature. The

solution was concentrated in vacuo to 300 cc.-andfilfered to removesodium bromide. The clear, light yellow solution was concentrated to 84-cc., precipitated with cc. of diethyl ether, aged at "5 C. for-3Ominutes, filtered and washed with ether. The solid product, which wasremoved by filtration, was essentially purets-bromopregnane-17u,21-diol-3,1 1,20-trione-2l-a'cetate [a] 112 (1%acetone). The 4,8-icdo compound which remained in the filtrate wasreduced to the initial starting material using zinc dust and acetic acidand recovered. The'yield of desired bromo compound, based on startingmaterial used, was 96.7%.

Example 6 .(A) A solution of 5.0 grams of chrome-pregnancpar d asdescribed in Example 2 in 10.0' ml. of pyridine and 40.0 ml. ofacetonitrile was held at 55 C. for 45 minutes. The resultant cortisoneacetate was removed by chloroform extractions. The chloroform solutionwas washed free of pyridine with 1.0 N sulfuric acid scrution. Thechloroform solution, washed with sodium bicarbonate solution and water,was evaporated to dryness. Theyield of pure cortisone acetate was 2.1%.p

(B) When the above procedure was repeated using 4 bromo-pr'egnane170:,21 diol 3,11,20 t'r'ione 21- acetate obtained according to Example1 which had .not been submitted to treatment with sodium bromide theyield of pure cortisone acetate was 17.3% (approximately an eight foldincrease) This example indicates the existence of the 4ut-b1'orno epimersince dehydrobromination of bromo compounds with pyridine is a knownreaction involving trans-elimination. The reaction of pyridine withuntreated i-bromopregnane 170;,21 diol 3,11,20 trione 21 acetate resultsin a yield of 17% of theeliininationp'r'oduc't', lthns indicating thepresence of the u-brotnoepimer in; :at least 17% (B above). The pyridinetreatment on the essentially p'ure p-brorno derivative (A above)produces only 2% of the elimination roduct, "cortisone acetateindicating that treatment of the epimeric mixture of 4-bromopregnaneswith sodium bromide converted it into the desired epimeric form. a

Any departure from the above description which eonforms to the presentinvention is intended to be included 7 salt wherein the halide componentof the salt has an atomic weight of from 35 to 127 to form thecorresponding compound having the halo group attached to such a carbonatom in the equatorial configuration.

2. The process of claim 1 wherein the treatment is carried out in apolar solvent.

3. A process which comprises treating a halogenation product containinga mixture of epimeric forms of a halogenated compound selected from thegroup consisting of p'r'egnenes, pregnanes and allopregnanes wherein thehalogen atoms are attached to the cyclopentanopolyhydrophenanthrenenucleus at a position alpha to a carbonyl group of said nucleus with ahalide salt wherein the halide component of the salt has an atomicweight of from 35 to 127 in a substantially neutral solution to convertthe mixture to the single equatorial form.

4. A process which comprises treating a halogenation product containinga mixture of epimeric forms of a halogenated compound selected from thegroup consisting of pregnenes, pregnanes and allopregnanes wherein thehalogen atoms are attached to the cyclopentanopolyhydrophenanthrenenucleus at a position alpha to a carbonyl group of said nucleus with aniodide salt in a substantially neutral solution to convert the halogroups in the polar configuration to iodo groups in theequatorialconfiguration.

5. A process which comprises treating a halogenation product containinga mixture of epimeric forms of a halogenated compound selected from thegroup consisting of 4-halo pregnenes, 4-halo pregnanes and 4-haloallopregnanes wherein the halogen atoms are attached to thecyclopentanopolyhydrophenanthrene nucleus at a position alpha to acarbonyl group of said nucleus with an iodide salt in a substantiallyneutral solution to convert the 4-halo group wherein the halogen atom isattached to the cyclopentanopolyhydrophenanthrene nucleus in the of4-bromo pregnenes wherein the bromo group is in a position alpha to acarbonyl group of the cyclcpentanopolyhydrophenanthrene nucleus and4-bromo pregnanes to the single 45 bromo compound wherein the bromogroup is attached to said nucleus in the equatorial coni figurationwhich comprises treating the mixture with a bromide salt in neutralsolution.

7. A process for converting a compound selected from the groupconsisting of 4-bromo pregnenes and 4-bromo pregnanes wherein the bromogroup is attached to the cyclopentanopolyhydrophenanthrene nucleus inthe polar configuration at a position alpha to a carbonyl group of saidnucleus to the corresponding 4-bromo compound wherein the bromo group isattached to said nucleus in the equatorial configuration which comprisestreating the 4-bromo compound wherein the bromo group is attached tosaid nucleus in the polar configuration with a bromide salt in neutralsolution.

8. A process for converting a compound selected from the groupconsisting of 4-bromo pregnenes and 4-bromo pregnanes' wherein the bromogroup is attached in the polar configuration to a carbon atom of thecyclopentanopolyhydrophenanthrene nucleus at a position alpha to acarbonyl group of said nucleus to the correspond- 9. A process whichcomprises treating a halogenation product containing a compound selectedfrom the group consisting of 3-keto-pregnenes, 3-keto-pregnanes and 3-keto-allopregnanes having a halo group of an atomic weight of from 35 to127 attached to at least one carbon atom ofthecyclopentanopolyhydrophenanthrene nucleus in the polar configuration,said halo group being attached to said nucleus in a position alpha tothe keto group suspended in a substantially neutral polar solventsolution with a halide salt wherein the halide component of the salt hasan atomic weight of from 35 to 127 to convert the compoundto thecorresponding compound having a halo group at such carbon atomin anequatorial configuration.

10. The process of claim 9 wherein the polar solvent is acetone.

11. The process of claim 9 wherein the polar solvent is a mixture ofacetone and water.

12. The process of claim 9 wherein the polar solvent is a mixture oftertiary butanol and chloroform.

13; The process of claim 9 wherein the polar solvent isdirnethylformarnide.

14. The process of claim 9 wherein the polar solvent is a mixture ofacetonitrile and chloroform.

15. The process of claim 9 wherein the halogenation product contains a4-bromo-3-keto-pregnane.

16. The process of claim 15 wherein the 4-bromo-3- keto-pregnane is4-bromo-pregnane-17a,21-diol-3,l1,20- trione-ZI-acetate.

17. A process which comprises treating a bromination product containinga mixture of epimeric forms of a compound selected from the groupconsisting of 4-bromo- 3-keto-pregnenes and 4-bromo-3-keto-pregnaneswith ten toforty percent by weight based on the weight of the compoundof a halide salt wherein the halide component of the salt has an atomicweight of from 35 to 127, in a substantially neutral solution to convertthe compound to the corresponding compound having a halo group at the4-position in the equatorial configuration.

18. A process for increasing the yield of compounds selected from thegroup consisting of 4-bromo-pregnenes and 4-bromo-pregnanes wherein the4-bromo group is attached to the cyclopentanopolyhydrophenanthrenenucleus in the equatorial configuration at a position alpha to acarbonyl group of said nucleus in the process for the mono-brominationof the 4-position of the compound which comprises reacting the crudeproduct formed as the result of the bromination process with a bromidesalt in a substantially neutral solution, and separating the 4-bromocompound wherein the 4-bromo group is attached to said nucleus in theequatorial configuration from the reaction mixture.

ing the 4-bromo compound wherein the bromo group is attached to saidnucleus in the equatorial configuration from the 4-iodo compound whereinthe iodo group is attached to said nucleus in the equatorialconfiguration thus formed and reducing the 4-iodo compound to thestarting compound by removal of the iodo group.

20. The process of claim 9 wherein the halogenation product contains a2,4-dibromo-3-keto-pregnane.

(References on following page) 9 10 References Cited in the file of thispatent 2,578,734 On Dec. 18, 1951 UNITED STATES PATENTS 2,594,079 HOIYSZ1954 2,203,611 Bockmuhl June 4, 1940 OTHER REFERENCES ,319,808 FCIIIhOlZMay 25, 1943 t 1 N t l P t R 1 t d t h 2,323,584 schoeuer y 1943 5Fleser e a aura roducs eae o enan m ,3d .27o-711949.c 'Pt.0fi. 2,374,683Julian May 1, 1945 f f ed PP m a 2,397,424 Marker Mar. 26, 1946

1. A PROCESS WHICH COMPRISES TREATING A COMPOUND SELECTED FROM THE GROUPCONSISTING OF PREGNENES, PREGNANES AND ALLOPREGNANES HAVING A HALO GROUPATTACHED IN THE POLAR CONFIGURATION TO A CARBON ATOM OF ACYCLOPENTANOPOLYHYDROPHENANTHRENE NUCLEUS, AT A POSITION ALPHA TO ACARBONYL GROUP OF SAID NUCLEUS, AT A POSITION SALT WHEREIN THE HALIDECOMPONENT OF THE SALT HAS AN ATOMIC WEIGHT OF FROM 35 TO 12( TO FORM THECORRESPONDING COMPOUND HAVING THE HALO GROUP ATTACHED TO SUCH A CARBONATOM IN THE EQUATORIAL CONFIGURATION.